INTRODUCTION — Acromegaly is a rare disorder characterized by excess secretion of growth hormone (GH) and its principal mediator, insulin-like growth factor (IGF) 1, whose production is stimulated by GH. An abnormal excess of GH is most commonly the result of a pituitary adenoma. A range of somatic and metabolic changes can occur in patients with acromegaly. Among these is an arthropathy, which is frequent in this condition and sometimes severe and disabling. The arthropathy may, in some cases, be a presenting feature of acromegaly [1,2].
The joint disorders associated with acromegaly are discussed here. The causes, other clinical manifestations, diagnosis, and treatment of acromegaly and GH excess in children and adolescents (pituitary gigantism) are reviewed in detail separately. (See "Causes and clinical manifestations of acromegaly" and "Diagnosis of acromegaly" and "Treatment of acromegaly" and "Pituitary gigantism".)
PATHOPHYSIOLOGY — Growth hormone (GH) and insulin-like growth factor (IGF) 1 are essential for normal growth, differentiation, and repair of cartilage and bone; however, excess GH and IGF-1, which are characteristic of acromegaly, lead to an arthropathy that resembles osteoarthritis (OA) but has several distinct features. The pathophysiology of acromegalic arthropathy is not fully understood. A common hypothesis is that there are two stages of arthropathy, with the first stage partially reversible on treatment [3,4]:
●In the first stage, excess GH and IGF-1 cause proliferation of articular chondrocytes and increased matrix production. This leads to thickened and abnormal articular cartilage and widening of the joint spaces. GH also affects connective tissue, promoting the growth of periarticular structures, which results in ligamentous laxity and joint instability. Synovial hypertrophy also occurs.
●In the second stage, cartilage damage occurs. Abnormalities in repair mechanisms, probably also due to excess GH, result in overproliferation of regenerating fibrocartilage, which may then become calcified and result in osteophyte formation. Subchondral cysts may also occur. Cartilage thickening may persist, but some patients may go on to have cartilage loss and joint space narrowing [5].
A study of 67 acromegalic patients in long-term remission found an association between the pretreatment levels of IGF-1 and the risk of OA of hip, hands, and cervical spine, although an association with pretreatment GH concentrations was not observed in that study [6]. Other research has found associations of baseline elevations of both GH and IGF-1 with the arthropathy [7].
EPIDEMIOLOGY — A degenerative arthritis, often referred to as osteoarthritis (OA) or secondary OA in the literature, is substantially more common in patients with acromegaly compared with the general population, but estimates of the prevalence of the arthritis among patients with acromegaly vary widely, from 30 to 70 percent or greater [2,8]. Arthropathy in acromegaly affects both males and females. In some studies [9,10], but not others [6,7], arthropathy is more frequent in females. The prevalence increases with age [7]. Definitions of acromegalic arthropathy vary widely from study to study, with some studies using reported symptoms and others radiology for diagnosis. Duration of acromegaly, disease activity and treatment, and age of patients may also differ between studies, making comparison difficult.
Early studies noted joint symptoms in the majority of patients with acromegaly [11]. However, a Belgian nationwide registry study of 418 patients with acromegaly in 2003 to 2004 reported symptoms of arthropathy in 46.7 percent [5]. In a retrospective study of 324 acromegalic patients presenting between 1981 and 2006, symptoms of arthropathy were noted in approximately 40 percent at diagnosis [12], with no significant difference between cohorts presenting in the early and later years of that study. A nationwide Danish cohort study of 405 acromegalic patients diagnosed between 1991 and 2010 showed the prevalence of arthropathy to be approximately double that of controls, both during the 3 years prior to diagnosis and from 1 to 30 years after diagnosis [7]. However, the definition of arthropathy in patients and controls was not given.
In a 1994 report of 500 patients with acromegaly, OA was noted in approximately 45 percent of cases, but whether this was radiographic or symptomatic was not described [13]. The prevalence of radiographic OA may be higher than symptomatic OA [6]. In a detailed study of 89 patients, despite adequate long-term control of acromegaly, radiographic evidence of OA was present at one or more joint sites in 99 percent of patients, and symptoms of pain and stiffness at one site or more were reported in 72 percent of patients overall [14]. OA was significantly more common and occurred at a younger age than in the control group.
The epidemiology of acromegaly is described separately. (See "Diagnosis of acromegaly", section on 'Epidemiology'.)
CLINICAL MANIFESTATIONS
Symptoms and physical findings — The main manifestations of the arthropathy in acromegaly include joint pain, particularly on activity [8,15-18]. The disease is typically polyarticular, and joint swelling and tightness, crepitus, and effusions have all been described. Hyperlaxity of the joints and spine can also occur, often followed by stiffness due to a combination of degenerative changes and thickening of subcutaneous tissues. In the hands, the symptoms may be complicated by coexistent carpal tunnel syndrome and related paresthesia. Synovial fluid is noninflammatory.
Spinal pain is common. Pain in the cervical and lumbar spine occurred in over 60 percent of patients in one study of patients with long-term controlled disease, while radiologic osteoarthritis (OA) at those sites was more frequent still, 91 and 82 percent, respectively [19]. In an older study of patients with active acromegaly, spinal pain occurred frequently, with 37 percent reporting neck pain, 17 percent reporting thoracic pain, and 50 percent reporting lumbar pain [20]. Kyphoscoliosis was reported in 21 percent, although it is not clear from this study what proportion of the kyphoscoliosis was degenerative or due to vertebral fractures. However, a subsequent study of 58 patients with acromegaly found vertebral fractures, predominantly thoracic, in 13.8 percent, thoracic kyphosis of >50 degrees in 36.8 percent, and scoliosis in 34.5 percent, all with a degenerative lumbar curve apex [21]. Abnormalities in bone density and skeletal fragility, including an increased risk of vertebral fractures, are discussed in detail separately. (See "Causes and clinical manifestations of acromegaly", section on 'Bone and joints'.)
Typical findings in acromegaly include widening of the hands and feet, with thickening of the fingers, toes, and soft tissues [8]. Changes develop gradually together with other manifestations of disease [22]. Disease affects large more than small joints, both weightbearing and nonweightbearing.
The sites of involvement, peripherally and axially, are variable:
●The peripheral joints most commonly affected symptomatically are the knees, hips, and shoulders, while involvement of the elbows, ankles, and hands is less common [18].
●Spinal pain and radiologic changes in the axial skeleton are frequent in both active and controlled disease [19,20]. Features of diffuse idiopathic skeletal hyperostosis (DISH) may be seen in 20 percent, correlating with impaired glucose tolerance [20]. (See "Diffuse idiopathic skeletal hyperostosis (DISH)".)
●Temporomandibular pain and malocclusion were reported in one-third of patients in one series [17].
●The acromegalic rosary is a palpable but not necessarily visible enlargement of the costochondral junctions. This finding occurred in 26 out of 27 subjects in one series [23].
The relationship between the severity of joint involvement and the severity and duration of acromegaly is uncertain. Arthropathy appears to be more common in older patients with a longer duration of disease [15,16]. However, there is wide variability, and arthropathy is the presenting complaint in some patients. Symptoms often persist after control of the excess hormone production. As an example, a study of 118 acromegalic patients in remission showed that 77 percent had self-reported joint problems, particularly of the hip and/or knee [9].
The diagnosis of acromegaly is often delayed, allowing the arthropathy to progress before treatment begins. A Spanish epidemiologic study reported that patients described symptoms of acromegaly an average of five years before diagnosis [24], while a smaller British prevalence study [25] described a delay of 1.5 to 15 years (median 4.5 years) before diagnosis. In this latter study, 28.6 percent of patients had joint symptoms at diagnosis.
In some studies [10,26], but not all [6], the progression of joint changes is related to body mass index (BMI). Differences in study populations, disease activity, and joints studied may explain this. For example, a study of 89 well-controlled acromegaly patients showed that in the hip, joint space narrowing was related to more active disease, but in the knee, it was associated with age, female sex, and knee surgery, but not with BMI [27]. Risk factors for primary OA may modify acromegalic arthropathy in the knee.
Radiographic progression of the arthropathy may not always reflect the progression of clinical symptoms. A prospective study of 31 patients with controlled acromegaly over a 9-year period showed significant radiographic progression of arthropathy in hips, knees, hands, and spine, although the progression of clinical symptoms was very variable and less frequent [28]. Higher baseline Kellgren and Lawrence scores at the hip predicted progression of hip OA in this study, while active disease duration, treatment modality, and pretreatment insulin-like growth factor (IGF) 1 levels did not.
Imaging findings — Characteristic changes on plain radiography include widening of joint spaces due to cartilage overgrowth and thickening of the soft tissues, which occurs in the early stages (image 1). The radiographic changes of the arthropathy in acromegaly are not necessarily associated with clinical symptoms and vary according to the stage of the arthropathy. The joint changes may progress to cartilage loss and features of degenerative joint disease, which are eventually indistinguishable from OA in many patients (image 2). There can be persistence of the characteristic radiographic findings of wide joint spaces, despite long-term control of acromegaly [14]; these changes may be associated with more self-reported pain [29]. In addition to these changes in the joints, thickening of the heel pad is often seen.
Radiology of the hip may show osteophytosis with preserved joint spaces or with joint space narrowing. Joint space narrowing occurs in approximately a third of patients with radiographic OA of the hip associated with acromegaly [27]. Similarly, in the knee, osteophytosis and preservation of joint spaces is common, but approximately half of those with features of OA of the knee will have joint space narrowing [27]. In the shoulder, there may be osteophytosis with normal or widened joint spaces, but loss of joint space or flattening of the humeral head occurs in a minority of patients [18].
Chondrocalcinosis has also been reported in association with acromegaly [30]. It was not clear, however, if this was a feature of acromegaly or a coincidental finding.
Changes of the arthropathy are also seen with magnetic resonance imaging (MRI). In a study that compared active and controlled acromegalic patients with controls with primary OA of the knee; acromegalic patients had fewer cysts and bone marrow lesions but a similar prevalence of osteophytosis and cartilage defects [4]. Cartilage thickness was greater in acromegalic patients compared with controls, and there was a small but significant increase in cartilage thickness in those with active acromegaly compared with controlled acromegaly.
DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS
●Diagnosis – Acromegalic arthropathy should be suspected in patients with known acromegaly and joint pain, often with stiffness, and considered in patients with osteoarthritis (OA) that appears premature or presents in association with carpal tunnel syndrome. The diagnosis of arthropathy due to acromegaly can be made most readily in a patient with a confirmed diagnosis of acromegaly; with symptoms of joint pain and stiffness; and with radiographic changes, especially in early disease, of apparent joint space widening and proliferative changes of bone, including prominent osteophytes. In later disease, the changes may be indistinguishable clinically from primary OA.
●Diagnostic evaluation – Diagnostic testing should include plain radiographs of symptomatic joints. MRI and ultrasound are not routinely used in diagnosis of acromegalic arthropathy but may be of value if symptoms are suggestive of other problems. For example, MRI can be used when clinically indicated to investigate coexistent pathology such as meniscal or ligament problems in the knee, and ultrasound may be helpful in evaluating coexistent shoulder tendon problems. The diagnostic evaluation of acromegaly is described separately. (See "Diagnosis of acromegaly".)
●Differential diagnosis – The arthropathy resembles generalized OA in that both upper and lower extremity and nonweightbearing joints can be affected, joint space narrowing can be present, and osteophyte formation is common. However, joint radiographs of the arthritis of acromegaly in the earlier stages show joint space widening and may show more osteophyte formation and less joint space narrowing at the hip and knee, compared with those of patients with primary generalized OA [31].
Symptoms of pain and weakness in the extremities due to carpal tunnel syndrome and a peripheral neuropathy (not limited to median neuropathy) may also occur in patients with acromegaly and are described separately. (See "Causes and clinical manifestations of acromegaly", section on 'Soft tissue and skin'.)
TREATMENT AND PROGNOSIS — Some symptoms of the arthropathy and much of the cartilaginous thickening may improve with treatment of the acromegaly [17,32]. A decrease toward normal of articular cartilage thickness has been documented ultrasonographically following 12 months of treatment with either octreotide [33] or lanreotide [34]. It is not clear whether medical or surgical treatment has more of an effect on progression of arthropathy. In one study, despite biochemical control, patients who received medical treatment with somatostatin analogues showed more progression of osteophytes and joint space narrowing than patients who were surgically cured [35]. Another retrospective study of 150 patients showed that good biochemical control, achieved using surgical and a variety of pharmacologic treatment, reduced the risk of diabetes and cardiovascular disease, but the risk of arthritis of spine, hips, hands, and knees appeared unaffected [36]. In this study, the risk of arthritis of "other" joints (these were not specified) increased with good biochemical control. By contrast, another study showed no effect of the type of treatment on arthropathy [6]. Early diagnosis and good disease control are advised to maximize any reversible aspects of the arthropathy. (See "Treatment of acromegaly".)
However, once bone damage has occurred, the arthritis is irreversible and tends to progress despite adequate control of growth hormone (GH) secretion, although there may be large variations between individuals [26,28]. In this setting, standard measures for the treatment of any degenerative arthropathy apply, including medications for pain relief, physiotherapy, occupational therapy, and, if necessary, joint replacement, as described in detail separately. (See "Overview of the management of osteoarthritis".)
Weight control is also advised, as a higher body mass index (BMI) may be associated with the progression of lower-limb osteoarthritis (OA) in acromegalic patients in remission, and also with more articular symptoms [26,37]. Intraarticular glucocorticoid injection appeared to be ineffective in one study [18]. It is important to assess routinely for musculoskeletal problems in acromegaly and to provide appropriate multidisciplinary treatment.
The arthropathy is not associated with increased mortality [38] but adversely affects quality of life [37]. As an example, a study of 58 patients with acromegaly over a five-year period found that 90 percent reported musculoskeletal pain associated with reduced quality of life and poor sleep, with 88 percent consulting their general practitioner for pain and over half consulting complementary medicine therapists [39].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and treatment of acromegaly".)
SUMMARY AND RECOMMENDATIONS
●Joint and spine disorders, which can be considered to be a type of secondary osteoarthritis (OA), are common in acromegaly and may dominate the clinical picture; these effects appear to be due to acceleration of the normal growth process by excess growth hormone (GH) and insulin-like growth factor (IGF) 1, which are essential for normal growth, differentiation, and repair of cartilage and bone. (See 'Pathophysiology' above.)
●The main manifestations of the arthropathy in acromegaly include joint pain, particularly on activity. Joint swelling and tightness, crepitus, effusions, and hyperlaxity of the joints and spine may occur. Spinal pain is common, and kyphoscoliosis may be seen. Vertebral fractures may contribute to kyphosis. The peripheral joints most commonly affected are the knee, shoulder, and hip. Axial involvement may affect any portion of the spine but is most common in the lumbar region, and features of diffuse idiopathic skeletal hyperostosis (DISH) may be present. (See 'Symptoms and physical findings' above.)
●The radiographic changes of the arthropathy in acromegaly vary according to the stage of the arthropathy. Widening of joint spaces due to cartilage overgrowth and thickening of the soft tissues occurs in the early stages (image 1), progressing to osteophyte formation, cartilage loss, and degenerative joint disease, which eventually may be indistinguishable from primary OA (image 2). In addition, thickening of the heel pad is often seen. (See 'Imaging findings' above.)
●The symptoms of the arthropathy and much of the cartilaginous thickening may improve with treatment of the acromegaly. In many patients, however, symptoms persist, and, once bone damage has occurred, the arthritis is irreversible and tends to progress despite adequate control of GH secretion. In this setting, standard measures for the treatment of any degenerative arthropathy apply. (See 'Treatment and prognosis' above.)
●The arthropathy of acromegaly has a significant impact on quality of life. It is important to assess routinely for musculoskeletal problems and to provide appropriate multidisciplinary treatment. (See 'Treatment and prognosis' above.)
